FDA Panel to Consider Two Cancer Drugs

WASHINGTON -- The FDA's Oncologic Drugs Advisory Committee will meet Thursday to weigh the evidence for approval of two different cancer therapies: tivozanib and a drug-device product combining melphalan (Alkeran) with a novel infusion kit.

However, overall survival -- the study's secondary endpoint -- was worse in the tivozanib arm compared with sorafenib, although not significantly so (28.8 months versus 29.3 months, respectively, P=0.11).

"We are asking the ODAC's advice on whether this single trial is sufficient to support approval of tivozanib for the indication of treatment of patients with advanced renal cell cancer or whether an additional trial is necessary before considering marketing approval," FDA reviewers wrote to advisory committee members.

The FDA expressed concern about the downward trend in overall survival in a single phase III study in a May 2012 meeting with the Cambridge, Mass., manufacturer, Aveo.

There are seven drugs approved to treat advanced renal cell carcinoma that inhibit vascular endothelial growth factor or its receptor like tivozanib does. All but one approval was based on improvement in progression-free survival.

The FDA failed to note any serious concerns in its 13-page briefing document for the drug. Tivozanib and sorafenib had a similar number of deaths due to adverse events (13 versus 12, respectively). The FDA is due to render its decision by July.

After its Thursday morning session on tivozanib, the ODAC will reconvene in the afternoon to assess a drug-device combination product to treat unresectable ocular melanoma that is metastatic to the liver -- a product that received a much harsher criticism from the FDA.

The ODAC will consider melphalan (Alkeran) -- which is already approved to treat multiple myeloma and ovarian cancer -- and the novel Melblez Kit. The device delivers the drug by percutaneous hepatic artery infusion. Blood is then filtered through a double-balloon catheter to extract the drug before returning clean blood to the body. Melphalan is delivered under general anesthesia every 4 to 8 weeks.

"Substantial and severe toxicity" was identified in all three trials, the FDA said, with 7% of patients dying from toxic reaction.

An analysis by the FDA found lot-by-lot differences in the risk of fatal side effects. The agency said in the briefing documents that the manufacturer, New York City's Delcath Systems, had not pinpointed the manufacturing attributes that correlate to clinically important adverse reactions.

"Until the critical quality attributes are defined and validated, FDA will require clinical testing to support approval of modifications of the device for changes in the hemoperfusion filter cartridge component, to characterize the risks of such changes," FDA reviewers stated.

The FDA wants a risk evaluation and mitigation strategy that contains elements to assure safe use, restricting prescribing to providers who have completed training on the device's safety.

There was less of a difference in overall progression-free survival (4.7 months vs. 1.6 months, P<0.0001), and no difference in overall survival (9.8 months vs. 9.95 months, P=0.20).

About 2,500 adults are diagnosed with ocular melanoma every year, and between a quarter and a half will develop metastatic disease within 2 years to 5 years. Metastases occur most in the liver, the FDA said.

The agency is seeking the ODAC's opinion on the safety and approval of the drug-device combination before rendering its decision, which is due by June. The agency isn't bound to follow the opinion of its advisory committees but usually does.

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